A Nonhuman Primate Model of Infant CMV Infection

描述（由申请人提供）：人类巨细胞病毒（HCMV）是世界上最常见的先天性感染，也是新生儿严重出生缺陷的主要感染原因。长期以来，HCMV一直被认为是对胎儿的一种传染性威胁，特别是在没有HCMV免疫力和怀孕期间原发性HCMV感染的妇女中。孕妇感染的主要来源是亚临床HCMV感染的儿童。先天性或围产期感染的儿童比在生命后期获得HCMV的人传播病毒的时间更长，滴度更高。为什么在产前或产后早期感染病毒的儿童释放病毒的时间更长，滴度更高，其机制尚不清楚。考虑到先天性HCMV感染相关的严重健康风险，打破亚临床感染儿童到孕妇到胎儿的传播链将对人类健康具有重要益处。与成人相比，这需要对幼儿的病毒-宿主相互作用有更好的了解。由于伦理原因，对新生儿的研究非常有限。因此，我们建议通过口服恒河巨细胞病毒（RhCMV）感染猕猴幼仔，建立非人类灵长类幼仔HCMV感染模型（Aim 1）。HCMV在成年猕猴中的发病机制模型已经建立，并与人类的HCMV感染非常相似。建立婴儿RhCMV感染模型将使我们有机会在保持病毒接种量、剂量和传播途径不变的情况下，确定婴儿和成人对RhCMV感染的特异性免疫反应的差异。潜在的假设是，HCMV感染患者的长期病毒学结果取决于最早的病毒-宿主相互作用。由于婴儿免疫系统不太成熟，整体的HCMV反应不太可能控制病毒复制。hcmv特异性CD4+T细胞在控制病毒复制中起重要作用。因此，我们提出了一种假设，即婴儿CD4+T细胞的有限功能能力，通过减少IFN-g的产生来评估，结合婴儿调节性T细胞的较高频率，会干扰有效的hcmv特异性CD4+T细胞的发育（目的2）。这一假设将在Aim 1中建立的RhCMV感染婴儿猕猴模型中得到验证。拟议研究的结果对于理解婴儿对其他传染性病原体的免疫反应以及如何预防儿童的致病性结果具有更广泛的重要性。因此，婴儿HCMV感染的非人类灵长类动物模型将是测试儿科抗病毒疗法和HCMV疫苗的有效性和安全性的独特资源。公共卫生相关性：人类巨细胞病毒（HCMV）是世界范围内最常见的先天性感染，是新生儿严重出生缺陷的主要感染原因。亚临床HCMV感染的儿童是孕妇HCMV感染的主要来源，因为感染HCMV的儿童比晚期感染HCMV的儿童传播病毒的时间更长，滴度更高。我们建议建立婴儿HCMV感染的非人灵长类动物模型，以促进我们对婴儿和成人HCMV发病机制中年龄相关差异的理解，并长期目标是打破从亚临床感染儿童到孕妇再到胎儿的传播链。

DESCRIPTION (provided by applicant): Human cytomegalovirus (HCMV) is the most common congenital infection worldwide and the primary infectious cause of serious birth defects in newborns. HCMV has long been recognized as an infectious threat to the fetus, particularly in women without HCMV immunity and who have a primary HCMV infection during pregnancy. The major source of infection for pregnant women are children with subclincal HCMV infection. Children that become infected congenitally or perinatally shed virus for longer periods of time and at higher titers than people that acquire HCMV later in life. The mechanism(s), why children who acquire the virus early in prenatal or post-natal life shed the virus longer and in higher titers are not known. Considering the severe health risks associated with congenital HCMV infection, breaking the chain of transmission from subclinically infected children to pregnant women to fetuses would have important benefits for human health. This requires a better understanding of virus-host interactions in very young children as compared to adults. For ethical reasons, studies in newborns are very limited. Thus, we propose to develop a nonhuman primate model of infant HCMV infection by orally infecting infant macaques with rhesus CMV (RhCMV) (Aim 1). A model of HCMV pathogenesis in adult macaques has been developed and closely mimics HCMV infection in humans. The establishment of an infant model of RhCMV infection will provide us with the opportunity to define differences in specific immune responses to RhCMV infection between infants and adults while keeping the virus inoculum, the dose, and the route of transmission constant. The underlying assumption is that long-term virological outcome in HCMV infected patients depends on the earliest virus-host interactions. As the infant immune system is less mature, the overall HCMV response is less likely to control virus replication. HCMV-specific CD4+T cells have been implicated to play an essential role in the control of virus replication. Thus, we present the hypothesis that a limited functional capacity of infant CD4+T cells, as assessed by reduced IFN-g production, combined with higher frequencies of regulatory T cells in infants interfere with the development of effective HCMV-specific CD4+T cells (Aim 2). This hypothesis will be tested in the infant macaque model of RhCMV infection established in Aim 1. The results of the proposed studies should be of broader importance for understanding infant immune responses to other infectious agents and how to prevent a pathogenic outcome in children. Thus, a nonhuman primate model of infant HCMV infection would be a unique resource to test the efficacy and safety of pediatric antiviral therapies and HCMV vaccines. PUBLIC HEALTH RELEVANCE: Human cytomegalovirus (HCMV) is the most common congenital infection worldwide and is the primary infectious cause of serious birth defects in newborns. Children with sublinical HCMV infection are the major source for HCMV infection in pregnant women because HCMV infected children shed virus for a longer time and at higher titers that people that acquire HCMV later in life. We propose to develop a nonhuman primate model of infant HCMV infection to advance our understanding of the age-related differences in HCMV pathogenesis in infants and adults with the longterm goal of breaking the chain of transmission from subclinically infected children to pregnant women to fetuses.